US2061557A - Anesthetic combinations containing, besides a local anesthetic agent, a vasoconstricting agent - Google Patents

Description

Patented Nov. 24, 1936 UNITED STATES 2,061,557 PATENT OFFICE ANESTHETIC COMBINATIONS CONTAINING, BESIDES A LOCAL ANESTHETIC AGENT, A VASOCONSTBIC'I'ING AGENT Max Bockmiihi, Frankfort-on-the-Main, and Otto Schaumann, .Wiesbaden, and Gustav Ehrhart and Leonhard Stein, Frankfort-on-the-Main,

Germany, assignors to Winthrop Chemical Company, Inc., New York, N. Y., a corporation of New York No Drawing. Application March 16, 1934, Serial No. 715,994. In Germany April 22, 1933 6 Claims.

HO CZECH-CZECH;

NH: HO

whereby the disadvantages of the local anesthetic combinations of this type, which have hitherto been known and employed, are obviated.

It is known to employ local anesthetic combinations containing, besides a local anesthetic agent, a vasoconstricting agent, the functions of the latter being to localize and prolong the anesthesia. The vasoconstricting agent, almost universally employed for this purpose, is epinephrin, i. e. 3.4-dihydroxy-phenyl-ethanol-methylamine of the following formula:

HO CHOHJIJHX NH'CH; o

For example a commonly used anesthetic combination of this type contains a local anesthetic agent such as the monohydrochloride of paraamino-benzoyl-diethyl-amino-ethanol which is generally known as Novocain or Procain and the vasoconstricting agent epinephrin.

There are, however, several disadvantages connected with the known anesthetic combinations containing the vasoconstricting agent, epinephrin. For example, it has been known for a long time that epinephrin is not ideal forthis purpose on account of the toxic by-effects which follow its use. Thus, in his Textbook of Exodontia" second edition, The C. V. Mosby Company, 1931, on page 92, Dr. Leo Winter states:

Uncomfortable and even alarming systemic reactions may occur at times following the subcutaneous administration of slightly excessive doses of epinephrin. The patient experiences a feeling of general distress and anxiety, becomes pale and suffers from a sensation of precordial A discomfort and pain, and shivers more or less iting, paresthesias, and heart-burn are other symptoms which occasionally occur. As a rule, these exaggerated and more or less alarming symptoms last only a very few minutes and have no serious results. However, such pronounced effects on the blood pressure and heart action may well prove harmful in cases of hypertension, arteriosclerosis, apoplexy, aneurysm, or feeble dilated heart.

In an article entitled Is Epinephrin Dangerous in Regional Local Anesthesia, Dr. La Rossa and Dr. Riccio (Paris Medical, vol. 15, 1926, page 341) state that if epinephrin is to be used, cases with cardio-vascular derangements and hyperthyroidism must be excluded, and that the patient should preferably be studied for tolerance to epinephrin by injection of small quantities of it.

Furthermore, Dr. Meeker and Dr. Frazer, (J. Pharmacol. & Exper. Therap., vol. 22, 1923, p. 390) state:

By means of its vasoconstricting power, epinephrin (adrenalin) retards absorption of the anesthetic drug as well as intensifies its anesthetic power, and in that regard is a factor of safety. Certain persons, however, aside from those with hyperthyroidism, are hypersensitive to its action; in them its use should be discarded. Toxic manifestations due to the absorption of epinephrin (adrenalin) may be marked palpita tion, a sense of oppression in the head and chest, tremor, pallor, nausea, and a sensation of fear and anxiety. No doubt the incidence of reactions to local anesthetics would be greatly reduced were it possible to dispense entirely with epinephrin (adrenalin) We have discovered that 3.4-dihydroxy-phenyl-alpha-propanol-amine of the following formula:

HO cnon-cn-cm NH: no

can be successfully employed as a substitute for epinephrin with local anesthetic agents to localize and prolong anesthesia and much to our surprise we have found that such combinations do not produce the above described toxic manifestations which follow the use of local anesthetic combinations with epinephrin and are tolerated without by-eifects in patients with hyperthyroidism or heart disease and in those cases with arteriosclerosis and high blood pressure. Furthermore, we have discovered that 10- cal anesthetic combinations with 3.4-dihydroxyphenyl-alpha-propanol-amine do not produce the collapse-like symptoms which follow the use of epinephrin in susceptible patients. The intensity and duration of anesthesia produced by local anesthetic combinations with 3.4-dihydroxy-phenyl-alpha-propanol-amine, employed as the vasoconstricting agent, are just as satisfactory as those produced by local anesthetic combinations with epinephrin.

3.4-dihydroxy-phenyl-alpha propanol amine is described in U. 8. Patent No. 1,044,778, issued November 19, 1912, as a product having the valuable therapeutic property of increasing the blood pressure in the same manner as the substance contained in the suprarenal glands. There is no disclosure in the literature concerning the use of this compound as a substitute for epinephrin in local anesthetic combinations.

By means of clinical experiments we have determined that the intensity and duration of anesthesia produced by the injection of an aqueous 2 per cent Novocain" solution containing, for instance, 3.4-dihydroxy-phenyl-alpha-propanolamine 1:10,000 are approximately the same as those produced by the injection of an aqueous Novocain solution with epinephrin 1:50,000.

By means of animal experiments we have determined that the intravenous toxicity of 3.4-dihydroxy-phenyl-alpha-propanol-amine is 7 to 10 times less than that of epinephrin. An aqueous 2 per cent Novocain solution with epinephrin 1:50,000 is definitely more toxic when injected intravenously into experimental animals than an aqueous 2 per cent Novocain" solution with 3.4- dihydroxy-phenyl-alpha-propanol-amine 1: 10,- 000..

Our new local anesthetic combinations with the vasoconstricting agent defined above are just as suitable for use by injection or local application to obtain local anesthesia as similar 10- cal anesthetic combinations prepared with epinephrin.

We have further discovered that aqueous solutions of our vasoconstricting agent are stable provided a water-soluble reducing agent is added to the solutions to prevent deterioration.

Our new anesthetic combinations can be marketed in any of the forms usual in the pharmaceutical practice, such as a powder, a tablet or a ready-to-use sterile solution in sealed glass ampules, cartridges or bottles without fear of decomposition. In addition sterile ready-touse aqueous solutions, or tablets of 3.4-dihydroxyphenyl-alpha-propanol-amine can be marketed so that the surgeon or dentist can prepare for his own use local anesthetic combinations with 3.4- dihydroxy-phenyl-alpha-propanol-amine by simply adding the desired amount of the sterile ready-to-use aqueous solution or the desired number of the tablets to any specified amount of 'a solution of a local anesthetic agent.

As the anesthetic agent in our new local anesthetic combinations with our vasoconstricting agent we prefer to use the monohydrochloride of para-aminobenzoyl-diethylamino-ethanol. Other alkamine esters of aromatic acids which may be used as the anesthetic agent are, for example,

. para-amino-benzoyl gamma butylamino propanol sulfate, para-amino-benzoyl-dimethylamino-methyl-butanol hydrochloride, para-butylamino-benzoyl-dlmethylamino-ethanol hydrochloride, para-amino-benzoyl-22-dimethyl-3-diethylamino-l-propanol hydrochloride, alphabutyl-oxy-cinchoninic acid gamma-diethyl-eth ylene-diamide hydrochlor and gamma-(2-methylpiperidino) -propyl-benzoate hydrochloride.

As a reducing agent in our ready-to-use aqueous solutions of 3.4-dihydroxy-phenyl-alpha-propanol-amine for use with local anesthetic agents or their solutions and aqueous solutions of our new anesthetic combinaHons containing, besides a local anesthetic agent, the vasoconstricting agent, inorganic water-soluble products may be employed. Preferably, we use the salts of the sulphurous and hyposulphurous acids or their derivatives, for example, sodium bisulfite, potassium bisulfite, sodium sulfite, formaldehyde bisulfite, sodium hydrosulfite, ace tone bisulphite, and formaldehyde sulfoxylate. The quantity of reducing agent required is relatively small and depends on the reducing agent employed. In general it is advisable to incorporate 50 milligrams to 200 milligrams in each 100 cc. of solution.

In order to more fully illustrate our invention the following examples are given, but it is to be understood that we do not restrict our invention to the specific compounds and proportions recited therein.

(1) One hundred grams of the monohydrochloride of para aminobenzoyl diethylaminoethanol are thoroughly mixed with l to 2 grams of 3.4-dihydroxy-phenyl-alpha-propanol amine as the hydrochloride or one of its other watersoluble salts. The uniform mixture is marketed either in the form of a powder or a tablet. An aqueous 2 per cent solution of the monohydrochloride of para aminobenzoyl diethylaminoethanol containing 3.4-dlhydroxy-phenyl-alphapropanol-amine from 1:10,000 to 1:5.000 is obtained by dissolving 2 grams of the powder or tablets in 100 cc. of water.

(2) Fifty to one hundred grams of the monohydrochloride of para-aminobenzoyl-diethylamino-ethanol and 0.5 to 1 gram of 3.4-dihydroxyphenyl-alpha-propanol-amine as the hydrochloride or one of its other water-soluble salts, are dissolved in 5000 cc. of 'sterile water or sterile 0.6 per cent. sodium chloride solution. Five to 10 grams of sodium bisulfite are then added as the reducing agent. The solution is then filtered.

(3) Five to ten grams of 3.4-dihydroxy-phenylalpha-propanol-amine hydrochloride are dissolved in 1000 cc. of sterile 0.6 per cent. sodium chloride solution. Two grams of acetone bisulfite are then added as the reducing agent. The solution is then filtered.

(4) grams of the hydrochloride of paraamino-benzoyl-diethylamino-ethanol, 2 grams of sodium chloride, 4 grams of potassium sulfate and 20cc. of a 1 per cent. solution of 3.4-dihydroxyphenyl-propanol-amine rendered acid by additionof hydrochloric acid are dissolved in such a quantity of distilled water that the whole volume amounts to 1000 cc.

If desired, 2 grams of acetone bisulfite may be added to the solution.

(5) 10 grams of the hydrochloride of paraaminobenzoyl-dimethylamino methylbutanol, 6 grams of sodium chloride and 0.2 gram of 3.4- dihydroxyphenyl-propanol-amine hydrochloride are dissolved in such a quantity of distilled water that the whole volume amounts to 1000 cc. 2 grams of acetone bisulfite may be added to the solution.

(6) 10 grams of beta-methoxy-ethylaminobenzoic acid-beta-piperidino-ethylester-monohydrochloride, 4 grams of sodium chloride, 2 grams of sodium bisulfite and 0.2 gram of 3.4-dihydroxyphenyl-propanol-amine hydrochloride are distassium sulfate solved in such a quantity of distilled water that the whole volume amounts to 1000 cc.

(7) 2 grams of 4-butylamino-benzoic acidbeta dimethylamino-ethylester monohydrochloride, 4 grams of sodium chloride, 4 grams of pond 0.2 gram of 3.4-dihydroxyphenyl-propanol-amine hydrochloride are dissolved in such a quantity of distilled water that the whole volume amounts to 1000 cc. A small quantity of sulfurous acid may be added to the solution. a

In order to prevent infection of the tissues it is essential that our aqueous solutions of 3.4-dihydroxy-phenyl-a.lpha-propanol-amine for use with local anesthetic agents or their solutions and the 1 aqueous solutions of our local anesthetic combinations with our vasoconstricting agent be sterile. We have found that sterility may be insured by filling sterile glass ampules, sterile cartridges or sterile bottles under aseptic conditions with the freshly prepared sterile solution. Our aqueous solutions of 3.4-dihydroxypenyl-alpha-propanolamine for use with local anesthetic agents or their solutions and the aqueous solutions of our local anesthetic combinations with 3.4-dihydroxyphenyl alpha propanol-amine are preferably sterilized by means of a Berkefeld filter or by autoclaving.

We have thoroughly tested our aqueous solutions of our vasoconstricting agent for use with local anesthetic agents or their solutions and our aqueous solutions of local anesthetic combinations with our vasoconstricting agent for sterility and stability. Relatively old solutions thereof in sealed glass ampules, cartridges and bottles have shown no change in color and have retained their full potency.

While we have described our improvements in great detail and with respect to preferred forms thereof, we do not desire to be limited to such details or forms since many modifications and changes may be made and the invention embodied in widely diflerent forms without departing from the spirit or scope of the invention in its broader aspects. Hence we desireto cover all modifications and forms coming within the scope or language of any one or more of the appended claims;

We claim:

1. Aqueous solutions comprising a water-soluble salt of 3.4-dihydroxy-phenyl-alpha-propano1- amine and a local anesthetic agent.

2. A sterile and stable aqueous solution of 0.5% to 1% of the hydrochloride of 3.4-dihydroxyphenyl-alpha-propanol-amine, 0.6% of sodium chloride and 0.1% to 0.2% of acetone bisulflte, and a local anesthetic agent.

3. A water-soluble powder or tablet for use as a local anesthetic composition and the active ingredients of which are l-2 parts of the hydrochloride of 3.4-dihydroxy-phenyl-alpha-propanolamine and 99 to 98 parts of the mono-hydroxychloride of para-amino-benzoyl-diazole-aminoethanol.

4. A sterile and stable aqueous solution of 1% to 2% of the mono-hydrochloride of para-aminobenzoyl diethyl-amino-ethanol and 0.01% to 0.02% of 3.4-dihydroxy-phenyl-a1pha-propanolamine, 0.6% of sodium chloride and 0.1% to 0.2% of sodium bisulflte.

5. A composition of matter consisting of compressed tablets containing 5-10 mgms. of 3.4-dihydroxy-phenyl-alpha-propanol-amine for use with local anesthetic agents or their solutions as a substitute for epinephrin to localize and prolong'anesthesia and to obviate the collapselike symptoms which follow the use of epinephrin in susceptible patients.

6. A composition of a matter comprising 3.4-

dihydroxy-phenyl-alpha-propanolamine and a lo-